Redox signaling is the
concept that electron-transfer processes play a key messenger role in biological
systems. It is involved in biological processes from neurotransmission to cancer.
Charles Darwin arguably provides the first illustration (melanin is
a free radical)

Darwin,
Charles, in The variation of animals and plants under domestication..
(1868 ),p322.

" Here is a
more curious case: white cats, if they have blue eyes, are almost always
deaf......"

" This case of correlation in
cats has struck many persons as marvellous. There is nothing unusual in the
relation between blue eyes and white fur; and we have already seen that the
organs of sight and hearing are often simultaneously affected. In the
present instance the cause probably lies in a slight arrest of
development in the nervous system in connection with the
sense-organs......."

Arguably, the first direct suggestion that redox processes are involved
in cell signaling is the Adrenochrome Hypothesis of Hoffer and Osmond. This
states that psychoactive oxidative products of catecholamines (adrenochromes)
play a role in schizophrenia and other neuropsychiatric diseases. While
the proposed mechanism is long-suplanted, the fundamental concept that
messenger-mediated oxidative stress is involved in neuropsychiatric disease
has proven correct. Similarly, in a feed-foreward process,
redox-signaling-mediated cell growth and proliferation combine with
genomic instability and Darwinian selection to drive many cancers.

"Role of
Active Oxygen Species in Ocular and Neurological
Diseases"

" Electronically-activated
species of oxygen such as superoxide or peroxide and their metabolic
products may play a key role in the etiology of certain disorders of the eye
and central nervous system. For example, in man, the chronic presence of
elevated systemic levels of agents such as urate, homocysteine, or copper
which can catalyze the production of such species and/or bind to melanin are
often associated with on or more of four characteristic signs. These are
psychotic behavior, movement disorders, deafness and pigmentary
abnormalities. Likewise, the enzymes superoxide dismutase (SOD) or catalase
are effective in the therapy of certain experimental lesions in animals such
as high pressure oxygen toxicity, corneal alkali burns, and formalin-induced
posterior segment uveitis. We
suggest that active oxygen metabolites act as specific intermediary
transmitter substances for a variety of biological processes including
inflammation, fibrosis, and possibly, neurotransmission.."
(emphasis-added)

In the discussion, we explain how we
came up with this strange idea-- sic:

"As should be clear from this
symposium, active oxygen species may play a key role in a large variety of
physiological processes including certain neurological syndromes,
inflammation, coagulation, scarring, drug toxicity, and so forth. While free
radical chemistry has long been perceived to have relevance to biology, a
key objection to assigning a role for electronically-active species in
processes such as those listed has been that these processes occur by very
organized and specific mechanisms. Thus, it is difficult to build models to
explain the apparent role of active oxygen species in such
mechanistically-complicated process based simply upon the chemical
reactivity of such species. Likewise, even evoking such things as the
Haber-Weiss reaction, the chemical reactivity of active oxygen species does
not correspond to their biological activity. Examples of this are the
apparent role of peroxide (rather than superoxide ) in OHP-induced
convulsions, antitumor agent toxicity, and acute burn-induced plasma volume
loss. Likewise, processes such as granulocyte lysosome release seem to be
dependent upon both superoxide and peroxide, others such as OHP-induced
convulsions only upon peroxide, and still others (e.g., platelet activation
) upon superoxide alone....One explanation for this data is that
various active oxygen species ( or such products as hydroperoxides ) may
act as specific transmitter
substances...."

As ref 1 and the CRC
review article below detail, peroxide has been known to modulate (e.g.) insulin
action since at least the mid 1970's. Likewise, in a 1970 publication*, we
noted the similarity of the choreoathetosis in the Lesch-Nyhan syndrome to the
side-effects of levodopa (implying a role for dopaminergic processes ion this
disease ) and related this to the electron-transfer properties of the
purines.

Similarly, in the
paper above, we refer in detail to Murad et als germinal work on nitric oxide and
cGMP as well as the modulatory effect of superoxide on platelet aggregation,
inflammation, tumor growth (some of which we discovered), etc.

However, this
abstract seems to be the first
explicit
suggestion that reactive oxygen species (ROS) in general play a specific
cellular messenger role for a broad range of processes, e.g. neurotransmission, cancer,
and inflammation. If this is not correct,
please let me
know.

The role of oxygen radicals as ubiquitus cellular
messengers is now generally-accepted. There is even a journal called
Antioxidants and Redox Signaling Thus, the
history of this hypothesis is illustrative of how peer-review sometimes fails
for novel ideas.

At the time, the reviewers universally considered the idea that free
radicals are messengers (now called "Redox Signaling") far too speculative,
though it is now obvious. Most likely, they have since changed their
minds.

Not to point fingers. There are some well-established researchers, who
don't credit Redox Signaling. But should it prove true, I'd like my discovery
claims honored, such as they are. Unless, naturally, anybody can find
anything earlier. In which case, I will readily give them credit
here.

By the way, I always thought pushing priority claims to be (well)
"tacky". But see what
happened when we did not push them, after anticipating the 2000 Nobel
Prize in Chemistry-winning discovery (high electrical conductivity in a
polyacetylene) by several years. Moreover, at least two other research
teams had reported high-conductivity in polyactylene derivative before us.
In fact, as Inzelt nores (1) conductive polymers had been synthesized, studied,
and even applied well before the Nobel winners

No, I am not griping about a lost Nobel-- far from it. The Nobel
committee took a wild swing here and not only missed our work, but the
real discoverers of high-conductivity in linear-backbone organic
polymers. True, we probably did report the first active organic electronic
device. Since organic electronics is part of "nanotechnology", ours is
also arguably the first Nanotech device.

Anyway, systemic problems with the way the Nobel committee does its
research makes such mistakes almost inevitable and common. We had the honor
of merely being the last (but definitely not the first) to report a high
conductivity organic polymer ( even a device ), before its rediscovery
earned others a Nobel prize. As detailed here,
the 1977 paper which won the 2000 Chemistry prize was mostly a reprise of a
series of 1963 papers by some Australian workers. Ironically, unheralded in
redox signaling research where it originated, our organic
semiconductor device is now on the short "Smithsonian
Chips" list of key discoveries in rather different fields. These are
semiconductor physics and integrated chip technology. In a rather distant
way, our device is the ancestor of your color cell-phone display.

Other than our work, the first specific reference to Redox Signaling seems
to be from
Bochner et al in 1984, five years after I presented it.
Again, if anybody knows different, please let me know so I can assign
proper credit, as we do the Aussies. "Citation amnesia" is a scientific sin.

In retrospect, I saw it because I am a pharmacologist--cellular
messengers are what we "do". Likewise, I had just finished a course in
pathology that made much of the fact that processes such as inflammation are
tightly-controlled by specific messenger-mediated mechanisms. Thus, the fact
that superoxide dismutase is antiinflammatory prima facia implies that
superoxide is a cellular messenger in inflammation, a point that only recently seems to have
become widely-appreciated.

One key event was the accidental discovery that SOD prevents diabetic stress-induced
hair loss in rodents. See this link. This discovery may
seem trivial, but the hair cycle is a very specific "developmental" process
and the hair follicle is an organ in miniature. E.g., unlike inflammation or
ischaemic injury, direct radical-induced tissue damage is much less a
confounding variable. Thus, superoxide almost certainly is a specific
messenger in the hair cycle. If here, then why not elsewhere? Interestingly,
the same experiment shows that oxidative stress is involved in the
pathogenesis of diabetes, now well-accepted.

Further, superoxide and nitric oxide are now known to have an
agonist/antagonist relationship in many systems. Completing the picture, the
hair-growth-stimulating agent miNOxidil seems to be a nitric oxide agonist.
Go here for a discussion.

However, because of such wild-eyed
speculation about how "free radicals are messengers", at the last moment,
this manuscript was omitted from the book coming out of this symposium, (
Pathology of Oxygen, Academic Press, 1982 ). I could not publish this
work and its supporting data elsewhere while it was pending publication
here.

Thus, publication took over four years.
Finally, so as not to draw more referee ire, our subsequent 1984 review
article on Free Radicals and
Human Disease (1) repeats the suggestion much more carefully.

For example, referring to ROS, we
note that " modulation of specific control mechanisms such as immunomodulator
proteins and lymphokines, cyclic nucleotides, or prostaglandin metabolism may
be of singular importance". Similarly, relative to ROS and inflammation, we
state " The specificity of such effects suggests that active oxygen
metabolites may be acting more as messenger substances than as non-specific
chemical reagents."

Concerning fibrosis-inducing drugs such
as bleomycin, we further note: " The stimulation of the fibrotic response by
these radical-generating agents may be a consequence of their common
interaction with existing modulator mechanisms coupling production of active
oxygen species by inflammatory cells with fibrocyte activation, collagen
production, and wound healing..." and so forth.. Additional details are found
in the references below.

This paper also seems to
contain the first suggestion that homocysteine pathogenesis relates to
oxidative stress. Similarly, this paper suggests that uric acid-mediated
oxidative stress plays a role in hyperuricemic diseases. Now, this is of
great interest in (e.g.) the pathogenesis of stroke, myocardial infarction, bipolar illness,
and metabolic syndrome.

Most especially, this
paper also implies that electronically-activated species might act as CNS
messengers, e.g., by activating psychoactive proteins or by modulating
neuromelanin function or by some dopaminergic process *. This is why the
title is "Electron-Transfer Processes.... and not "Free Radical Processes...."
I still subscribe to this general model.

For our later CRC
Handbook review on "Free
Radicals and Human Disease",go here.

Currently, I'm a practicing physician.
I also have graduate degrees in pharmacology/toxicology and biophysics and did
a residency in Pathology. So I have a little broader background than most free
radical researchers.

My main scientific interest is
nitrone and nitroxide drugs for degenerative diseases such as stroke and
ischaemic injury. I hold some
primary patents on these. I am especially interested in pattern hair loss, an
excellent model both for age-related chronic degenerative diseases in general
and for redox signaling.